Hidróxido de alumínio em suspensão de 60 mg/mL para o tratamento de gastrite, úlceras gástricas e duodenais e esofagite de refluxo / Aluminum hydroxide in suspension of 60 mg/mL for the treatment of gastritis, gastric and duodenal ulcers and reflux esophagitis

INTRODUÇÃO: Há um grupo de doenças cuja patogênese está relacionada ao ácido gástrico, tanto em função de distúrbios na secreção, quanto da ação direta desse composto na mucosa do trato gastrintestinal. A hipersecreção gástrica está diretamente relacionada à patogênese de úlceras duodenais, e a magnitude da supressão ácida é diretamente proporcional à taxa de recuperação dessas lesões. Já nas úlceras gástricas, enquanto a secreção gástrica se mantém em níveis normais, a inibição da secreção por tempo e em magnitude adequados está associada a melhoria nas taxas de recuperação e cura. O mesmo ocorre para doença do refluxo gastroesofágico. A utilização de antiácidos como o hidróxido de alumínio é preconizada nos casos com sintomas leves a moderados e infrequentes em associação ao tratamento com anti-secretores. Faz-se nesse relatório uma revisão rápida da literatura sobre a utilização de hidróxido de alumínio no tratamento dessas doenças. PERGUNTAS: Hidróxido de alumínio em suspensão é eficaz e seguro para o tratamento de gastrite, úlceras gástricas e duodenais e doença do refluxo esofágico? EVIDÊNCIAS CLÍNICAS: Em gastrite a utilizaçã de hidróxido alumínio ou desse em associação a hidróxido de magnésio em adultos em suspensão entre 6 a 7 vezes ao dia por 4 a 8 semanas foi mais eficaz que placebo e igualmente eficaz a misoprostol, antagonistas dos receptores H2, sucralfato e hidróxido de magnésio no alívio completo ou redução da severidade de sintomas relacionados à gastrite tais como dor abdominal; pirose; regurgitação; náusea; êmese. No tratamento de úlceras pépticas em adultos (gástrica e duodenal) a utilização de hidróxido de alumínio isolado ou em associação com hidróxido de magnésio em doses de 10 a 30 mL entre uma e 8 vezes ao dia por 4 a 8 semanas foi igualmente ou mais eficaz que placebo na diminuição dos episódios e severidade da dor e do tempo com dor. A utilização de ranitidina em associação a antiácido a base de hidróxido de alumínio não foi diferente do antiácido isolado na diminuição da intensidade de dor. Da mesma forma não se identificaram diferenças entre o antiácido e cimetidina de 800 a 1.200 mg por dia por 4 a 8 semanas na redução de dor dispepsia e pirose; ou entre o antiácido isolado e a associação com oxetacaína. No tratamento de doença do refluxo gastresofágico em adultos a utilização de hidróxido de alumínio e magnésio (1,5 g (15 mL) uma vez ao dia por 12 semanas) foi mais eficaz que placebo na redução dos episódios de refluxo, do número de episódios de refluxo com mais de cinco minutos e do tempo médio dos episódios. O número de pacientes com pH esofágico menor do que 4 diminuiu mais no grupo que recebeu o antiácido. Não houve diferença estatisticamente significativa quando se compararam tratamentos com ranitidina na dose de 300 mg ao dia e antiácido a base de hidróxido de magnésio e alumínio (10 mL sete vezes ao dia por 6 semanas). ANÁLISE DE IMPACTO ORÇAMENTÁRIO: O impacto orçamentário relacionado à aquisição da suspensão de 60 mg/mL é de cerca de 1,5 milhões por ano para o período de 2023 a 2027. O impacto total para o período foi de 7,6 milhões. CONSIDERAÇÕES FINAIS: Segundo as especificações da Farmacopeia brasileira é permitida uma variação de 10% para mais ou para menos na quantidade de alumínio na suspensão. Entende-se que entre as suspensões com concentrações de 6,15% e 6,00% há uma variação de 2,5% da quantidade de hidróxido de alumínio para menos, o que está dentro da faixa de variação permitida mínima para o produto segundo os critérios da farmacopeia. Segundo esses critérios espera-se que esses produtos apresentem a mesma eficácia em termos de capacidade de neutralização ácida. Segundo a evidência constante em estudos controlados randomizados, tratamentos em adultos com hidróxido de alumínio em suspensão isolado ou em associação ao hidróxido de magnésio são mais eficazes que placebo e não diferentes de antagonistas do receptor H2 na redução ou resolução de sintomas relacionados à gastrite, úlcera duodenal e doença do refluxo gastresofágico. Na população pediátrica há pouca ou nenhuma evidência que suporte o uso dessa medicação. Esse medicamento pode ser utilizado como alternativa, em adultos intolerantes aos tratamentos com medicamentos anti-secretores ácidos. Entretanto, esses estudos, em sua maioria, foram publicados nas décadas de 70 e 80 e estão relacionados a um alto risco de viés. PERSPECTIVA DO PACIENTE: Foi aberta chamada pública para inscrição de participantes na perspectiva do paciente para discussão deste tema, entre os dias 10/03/2023 e 20/03/2023. Duas pessoas se inscreveram, contudo, não deram seguimento ao processo preparatório. RECOMENDAÇÃO PRELIMINAR DA CONITEC: Os membros do Comitê de Medicamentos presentes na 117ª Reunião Ordinária da Conitec, realizada no dia 28 de março de 2023, deliberaram por unanimidade recomendar a incorporação da suspensão oral de hidróxido de alumínio na concentração de 60,0 mg/mL. CONSULTA PÚBLICA: A Consulta Pública nº 10/2023 foi realizada entre os dias 19/04/2023 e 08/05/2023. Foi recebida uma contribuição pelo formulário para contribuições técnico-científicas, mas nenhuma pelo formulário para contribuições sobre experiência ou opinião de pacientes, familiares, amigos ou cuidadores de pacientes, profissionais de saúde ou pessoas interessadas no tema. Na contribuição recebida identificou-se posicionamento favorável à recomendação preliminar do Comitê de Medicamentos, apesar da manifestação desfavorável constante no formulário. Dessa forma, declarou-se que o hidróxido de alumínio é um medicamento eficaz para o tratamento de gastrite, úlceras gástricas e duodenais e esofagite de refluxo. Disse também que a única razão para a exclusão desse medicamento do SUS fora a caducidade do registro sanitário, complementando que a nova formulação discutida neste relatório fora aprovada pela Agência Nacional de Vigilância Sanitária (Anvisa) para comercialização. Sobre o impacto orçamentário não houve contribuições recebidas por meio de consulta pública, entretanto, na apreciação inicial do tema o Comitê solicitou que se refizesse a projeção de impacto orçamentário incluindo a estimativa do quantitativo de pacientes que, devido à exclusão da ranitidina do SUS, passariam a utilizar, como substituto terapêutico, o hidróxido de alumínio. Dessa forma elaborou-se nova análise de impacto orçamentário. Pela nova projeção haveria um aumento médio de R$ 100.000,00 (8%) pela absorção da demanda criada pela exclusão da ranitidina do SUS (novos valores no compêndio econômico). RECOMENDAÇÃO FINAL DA CONITEC: O Comitê de Medicamentos da Conitec, em sua 119ª Reunião Ordinária, no dia 31 de maio de 2023, deliberou por unanimidade recomendar a incorporação da suspensão oral de hidróxido de alumínio na concentração de 60,0 mg/mL no SUS. Os membros do Comitê de Medicamentos consideraram que não houve novas evidências que pudessem alterar a recomendação preliminar. Por fim, foi assinado o Registro de Deliberação nº 830/2023. DECISÃO: Incorporar, no âmbito do Sistema Único de Saúde - SUS, a suspensão oral de hidróxido de alumínio na concentração de 60 mg/mL, publicada no Diário Oficial da União nº 140, seção 1, página 125, em 25 de julho de 2023.

Long-acting injectable in situ gel of rasagiline: a patented product development.

Rasagiline has a certain potential in neuroprotection and delaying the progression of Parkinson's disease (PD). However, the poor pharmacokinetics (PK) characteristics of conventional oral tablets and poor medication compliance limit the optimal efficacy of rasagiline. Based on this, we designed and optimized a sustained-release rasagiline in situ gel based on in vitro release and in vivo PK results. Among them, we found for the first time that aluminum hydroxide can effectively shorten the lag phase and promote early and late release, making the daily release more uniform. After subcutaneous administration of the optimized gel formulation at a monthly dose, the Cmax (64 ng/ml) was lower than that of free rasagiline (494 ng/ml) administered subcutaneously at a daily dose and comparable to that of oral administration of Azilect® (59.1 ng/ml) at a daily dose. In the meantime, the plasma concentration of rasagiline was mainly maintained at 5-10 ng/ml for about 1 month, and the active metabolite 1-aminoindane in plasma was also able to maintain a steady state. The rasagiline in situ gel has suitable viscosity and injectability, good repeatability of subcutaneous injection, and controllable impurities and can achieve sustained release in vivo with small burst release, which may have the clinical application advantages of maximizing the disease-modifying effect of rasagiline and improving medication compliance. The rasagiline in situ gel was optimized through the feedback of in vitro release and in vivo pharmacokinetics (PK), in which the addition of aluminum hydroxide had a modulating effect on uniform release. The gel has low burst release and maintains steady-state blood drug concentration for about 1 month.

Acid Neutralization and Immune Regulation by Calcium-Aluminum-Layered Double Hydroxide for Osteoporosis Reversion.

Osteoporosis is a kind of global chronic bone disease characterized by progressive loss of bone mass and bone quality reduction, leading to a largely increased risk of bone fragility. In clinics, the current treatment of osteoporosis relies on the inhibition of bone damage by osteoclasts but ignores the function of immune cells in the progress of osteoporosis, leading to much compromised therapeutic efficacy. In this work, a highly effective osteoporosis-immunotherapeutic modality is established for the treatment of osteoporosis based on acid neutralization in synergy with immune microenvironment regulation by a specially designed nanocatalytic medicine, calcein functionalized calcium-aluminum-layered double hydroxide (CALC) nanosheets. Briefly, the mildly alkaline CALC nanosheets could neutralize the acidic microenvironment of osteoporosis accompanying the acidity-responsive LDH degradation. Subsequently, calcium phosphate nanoparticles (CAPs) are generated by the reaction between the released Ca2+ from LDH degradation and endogenous phosphates, resulting in M2 phenotype anti-inflammatory differentiation of bone macrophages through a c-Maf transcriptional factor pathway and the following activity enhancements of regulatory T cells (Treg) and the deactivation of T helper 17 cells (TH17). Both in vitro and in vivo results show an excellent therapeutic efficacy on osteoporosis featuring a significant BV/TV (%) enhancement of femurs from 6.2 to 10.7, demonstrating high feasibility of this therapeutic concept through the combined acid neutralization and immune regulation. Such an inorganic nanomaterial-based strategy provides a novel, efficient, and biosafe therapeutic modality for intractable osteoporosis treatment, which will benefit patients suffering from osteoporosis.

Yeast Shells Encapsulating Adjuvant AS04 as an Antigen Delivery System for a Novel Vaccine against Toxoplasma Gondii.

Toxoplasma gondii (T. gondii) infection causes severe zoonotic toxoplasmosis, which threatens the safety of almost one-third of the human population globally. However, there is no effective protective vaccine against human toxoplasmosis. This necessitates anti-T. gondii vaccine development, which is a main priority of public health. In this study, we optimized the adjuvant system 04 (AS04), a vaccine adjuvant constituted by 3-O-desacyl-4'-monophosphoryl lipid A (a TLR4 agonist) and aluminum salts, by packing it within natural extracts of ß-glucan particles (GPs) from Saccharomyces cerevisiae to form a GP-AS04 hybrid adjuvant system. Through a simple mixing procedure, we loaded GP-AS04 particles with the total extract (TE) of T. gondii lysate, forming a novel anti-T. gondii vaccine GP-AS04-TE. Results indicated that the hybrid adjuvant can efficiently and stably load antigens, mediate antigen delivery, facilitate the dendritic uptake of antigens, boost dendritic cell maturation and stimulation, and increase the secretion of pro-inflammatory cytokines. In the mouse inoculation model, GP-AS04-TE significantly stimulated the function of dendritic cells, induced a very strong TE-specific humoral and cellular immune response, and finally showed a strong and effective protection against toxoplasma chronic and acute infections. This work proves the potential of GP-AS04 for exploitation as a vaccine against a range of pathogens.

Does Pepsin Saliva Concentration (Peptest™) Predict the Therapeutic Response of Laryngopharyngeal Reflux Patients?

OBJECTIVE: To study the profile and the therapeutic response of patients with laryngopharyngeal reflux (LPR) at the hypopharyngeal-esophageal multichannel intraluminal impedance-pH monitoring (HEMII-pH) according to the initial pepsin saliva concentration. METHODS: From January 2018 to January 2020, patients with positive LPR diagnosis at the HEMII-pH were consecutively recruited from 3 European Hospitals. Saliva pepsin concentration (Peptest™) was measured during the HEMII-pH testing period and patients were classified into 2 groups: negative versus positive Peptest. The clinical outcomes, that is, gastrointestinal and HEMII-pH findings, reflux symptom score-12 (RSS-12), and 3-month therapeutic response, were compared between groups. RESULTS: A total of 124 patients completed the study. Among them, 30 patients had negative Peptest. Pharyngeal reflux events occurred outside 1-hour post-meal time in 74.0%, after the meals in 20.5% and nighttime in 5.5%. The pepsin saliva level was not significantly associated with the reflux events preceding the sample collection. Patients with positive Peptest had better improvement of RSS-12 digestive and respiratory subscores and oral, pharyngeal, and laryngeal findings compared with patients with negative Peptest. CONCLUSION: Patients with high saliva pepsin concentration had no stronger gastrointestinal, HEMII-pH, or clinical outcomes compared with those with low or undetectable saliva pepsin concentration.

Development of CpG-adjuvanted stable prefusion SARS-CoV-2 spike antigen as a subunit vaccine against COVID-19.

The COVID-19 pandemic is a worldwide health emergency which calls for an unprecedented race for vaccines and treatment. In developing a COVID-19 vaccine, we applied technology previously used for MERS-CoV to produce a prefusion-stabilized SARS-CoV-2 spike protein, S-2P. To enhance immunogenicity and mitigate the potential vaccine-induced immunopathology, CpG 1018, a Th1-biasing synthetic toll-like receptor 9 (TLR9) agonist was selected as an adjuvant candidate. S-2P in combination with CpG 1018 and aluminum hydroxide (alum) was found to be the most potent immunogen and induced high titer of neutralizing antibodies in sera of immunized mice against pseudotyped lentivirus reporter or live wild-type SARS-CoV-2. In addition, the antibodies elicited were able to cross-neutralize pseudovirus containing the spike protein of the D614G variant, indicating the potential for broad spectrum protection. A marked Th1 dominant response was noted from cytokines secreted by splenocytes of mice immunized with CpG 1018 and alum. No vaccine-related serious adverse effects were found in the dose-ranging study in rats administered single- or two-dose regimens of S-2P combined with CpG 1018 alone or CpG 1018 with alum. These data support continued development of CHO-derived S-2P formulated with CpG 1018 and alum as a candidate vaccine to prevent COVID-19 disease.

Efficacy of GAD-alum immunotherapy associated with HLA-DR3-DQ2 in recently diagnosed type 1 diabetes.

AIMS/HYPOTHESIS: The aim of this study was to determine if retention of C-peptide following immunotherapy using recombinant GAD65 conjugated to aluminium hydroxide (GAD-alum) is influenced by HLA risk haplotypes DR3-DQ2 and DR4-DQ8. METHODS: HLA-dependent treatment effect of GAD-alum therapy on C-peptide retention in individuals with recent-onset type 1 diabetes was evaluated using individual-level patient data from three placebo-controlled, randomised clinical trials using a mixed repeated measures model. RESULTS: A significant and dose-dependent effect was observed in individuals positive for the genotypes that include HLA-DR3-DQ2 but not HLA-DR4-DQ8 and in the broader subgroup of individuals positive for all genotypes that include HLA-DR3-DQ2 (i.e. including those also positive for HLA-DR4-DQ8). Higher doses (three or four injections) showed a treatment effect ratio of 1.596 (95% CI 1.132, 2.249; adjusted p = 0.0035) and 1.441 (95% CI 1.188, 1.749; adjusted p = 0.0007) vs placebo for the two respective HLA subgroups. CONCLUSIONS/INTERPRETATION: GAD65-specific immunotherapy has a significant effect on C-peptide retention in individuals with recent-onset type 1 diabetes who have the DR3-DQ2 haplotype. Graphical abstract.

Immunogenicity and Safety of a Tetravalent Recombinant Subunit Dengue Vaccine in Adults Previously Vaccinated with a Live Attenuated Tetravalent Dengue Vaccine: Results of a Phase-I Randomized Clinical Trial.

New dengue vaccines are needed to prevent this globally expanding vector-borne disease. The V180 vaccine candidate consists of four recombinant, soluble, dengue virus envelope glycoproteins and has been previously evaluated in two clinical trials for safety and immunogenicity in Flavivirus-naive participants (NCT01477580 and NCT0093642). Here, we report on a randomized, placebo-controlled, double-blind study of the safety and immunogenicity of the V180 vaccine in subjects who have previously received the live attenuated tetravalent vaccine (LATV) developed by the National Institute of Allergy and Infectious Diseases (protocol #V180-002 [CIR-301]). The study was designed to evaluate whether this recombinant subunit vaccine could boost the neutralizing antibody responses induced by dengue LATV. Twenty participants who had previously received one or two doses of dengue LATV were randomized and received a single dose of V180 nonadjuvanted (N = 8), V180 adjuvanted with Alhydrogel™ (aluminum hydroxide gel, Brenntag Biosector, Frederikssund, Denmark) (N = 8), or placebo (N = 4). Immunogenicity was measured using a plaque reduction neutralization test at days 1, 15, 28, and 180 after vaccination. In addition, vaccine safety (solicited and unsolicited adverse events) was assessed using a vaccination report card for 28 days following vaccination, and serious adverse events were captured from the time of informed consent through the final study visit at 6 months after vaccination. The results of the study demonstrate that the V180 vaccine is generally well tolerated and immunogenic in these dengue-seropositive volunteers.

Randomised clinical trial: the effectiveness of Gaviscon Advance vs non-alginate antacid in suppression of acid pocket and post-prandial reflux in obese individuals after late-night supper.

BACKGROUND: Late-night supper increases the risk of postprandial reflux from the acid pocket especially in obesity. An alginate-based, raft-forming medication may be useful for obese patients with GERD. AIMS: To compare the efficacy of Gaviscon Advance (Reckitt Benckiser, UK) and a non-alginate antacid in post-supper suppression of the acid pocket and post-prandial reflux among obese participants. METHODS: Participants underwent 48 h wireless and probe-based pH-metry recording of the acid pocket and lower oesophagus, respectively, and were randomised to single post-supper (10 pm) dose of either Gaviscon Advance or a non-alginate antacid on the second night. Primary outcomes were suppression of median pH of acid pocket and lower oesophagus, measured every 10-minutes post-supper for 1 h. Secondary outcomes were suppression of % time pH < 4 at lower oesophagus and improvement in frequency and visual analogue score (VAS) of regurgitation. RESULTS: Of the 81 screened participants, 55 were excluded and 26 (mean age 33.5 years, males 77.8% and BMI 32.8 kg/m2 ) were randomised to Gaviscon Advance (n = 13) or antacid (n = 13). Median pH of the acid pocket but not the lower oesophagus was suppressed with Gaviscon Advance vs antacid (all P < 0.04) Gaviscon Advance but not antacid significantly reduced in % time pH < 4, symptom frequency and VAS on day 2 vs day 1 (all P < 0.05). CONCLUSIONS: Among obese individuals, Gaviscon Advance was superior to a non-alginate antacid in post-supper suppression of the acid pocket. (Clinical trial registration unique identifier: NCT03516188).

The signal transducer and activator of transcription 6 (STAT-6) mediates Th2 inflammation and tissue damage in a murine model of peanut-induced food allergy

Introduction: Food allergies are inflammatory conditions mediated by Th2 and probably STAT-6 dependent immune responses. Objective and design: Here we investigated the role of Signal Transducer and Activator of Transcription 6 (STAT-6) in development of inflammation in peanut allergy. Methods: To induce food allergy, wild-type (WT) and mice deficient for STAT-6 (Stat6-/-) were sensitized with peanut proteins and challenged with peanut seeds. Results: WT animals lost weight and refused the peanut diet, in contrast to Stat6-/- mice, which had a better maintenance of body weight and more regular seeds' consumption. The augmented peanut-specific IgG, IgG1 and IgE in the allergic WT was abolished in Stat6-/- animals that also presented increased IgG2a. There was an overall reduction in the gut mediators in the absence of STAT-6, including those related to inflammatory and Th2 responses, in contrast to a rising counter regulatory and Th1 reaction in Stat-6-/- mice. These animals had IFN-γ and IL-10 similar to WT after the four-week challenge. Most interestingly, Stat-6-/- mice had no intestinal damage, in contrast to WT animals, which had inflammatory infiltrate, tissue destruction, epithelial exulceration, edema, congestion and loss of villous architecture in the small gut segments. Conclusions: STAT-6 plays an important role in the establishment of the Th2 inflammatory responses and intestinal damage in peanut allergy

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Electroacupuncture plus on-demand gastrocaine for refractory functional dyspepsia: Pragmatic randomized trial.

BACKGROUND AND AIM: Treatment options for functional dyspepsia (FD) refractory to pharmacological treatments are limited but the effectiveness of electroacupuncture (EA) is uncertain. We assessed the effectiveness of EA combined with on-demand gastrocaine. METHODS: We conducted a single-center, assessor-blind, randomized parallel-group 2-arm trial on Helicobacter pylori negative FD patients of the postprandial distress syndrome subtype refractory to proton pump inhibitor, prokinetics, or H2 antagonists. Enrolled participants were block randomized in a 1:1 ratio, with concealed random sequence. The treatment and control groups both received on-demand gastrocaine for 12 weeks, but only those in treatment group were offered 20 sessions of EA over 10 weeks. The primary endpoint was the between-group difference in proportion of patients achieving adequate relief of symptoms at week 12. RESULTS: Of 132 participants randomly assigned to EA plus on-demand gastrocaine (n = 66) or on-demand gastrocaine alone (n = 66), 125 (94.7%) completed all follow-up at 12 weeks. The EA group had a compliance rate 97.7%. They had a significantly higher likelihood in achieving adequate symptom relief at 12 weeks, with a clinically relevant number needed to treat (NNT) value of 2.36 (95% CI: 1.74, 3.64). Among secondary outcomes, statistically and clinically significant improvements were observed among global symptom (NNT = 3.85 [95% CI: 2.63, 7.69]); postprandial fullness and early satiation (NNT = 5.00 [95% CI: 2.86, 25.00]); as well as epigastric pain, epigastric burning, and postprandial nausea (NNT = 4.17 [95% CI: 2.56, 11.11]). Adverse events were minimal and nonsignificant. CONCLUSION: For refractory FD, EA provides significant, clinically relevant symptom relief when added to on-demand gastrocaine (ChiCTR-IPC-15007109).

Two placebo-controlled crossover studies in healthy subjects to evaluate gastric acid neutralization by an alginate-antacid formulation (Gaviscon Double Action).

OBJECTIVE: To investigate the intragastric acid neutralization activity of a combined alginate-antacid formulation. SIGNIFICANCE: Published studies have investigated the reflux-suppressing alginate component of Gaviscon Double Action (Gaviscon DA; RB, UK) but intragastric acid neutralization activity of the antacid component has not been evaluated in vivo. METHODS: Intragastric pH monitoring, using a custom-made 10-electrode catheter, was evaluated in a two-part exploratory study in healthy subjects; Part I (n = 6) tested suitability of the catheter using antacid tablets (Rennie; Bayer, Germany); Part II (n = 12) evaluated gastric acid neutralization activity of Gaviscon DA liquid (20 ml) versus placebo in fasted subjects using a randomized, open-label, crossover design. The primary endpoint was the percentage of time that intragastric pH ≥4 was measured during 30 min post-treatment. A confirmatory study of identical design was subsequently conducted (n = 20). RESULTS: Monitoring pH using the multielectrode catheter was a viable approach, directly detecting changes in intragastric pH following a single dose of antacid tablets. In the exploratory study, the percentage of time that pH ≥4 during 30 minutes post-treatment was 46.8% with Gaviscon DA liquid versus 4.7% with placebo (p = 0.0004). These findings were supported by the confirmatory study, where pH ≥4 was recorded 50.8% of the time with Gaviscon DA versus 3.5% with placebo (p = 0.0051). In this study, Gaviscon DA was safe and well tolerated. CONCLUSIONS: These studies demonstrate the effective acid neutralizing capacity of Gaviscon DA versus placebo in healthy, fasted subjects. This adds to the evidence base for the combination of alginates and antacids.

Therapeutic potential of topically administered γ-AlOOH on 2,4-dinitrochlorobenzene-induced atopic dermatitis-like lesions in Balb/c mice.

Boehmite (γ-AlOOH) has a wide range of applications in a variety of industrial and biological fields. However, little is known about its potential roles in skin diseases. The current study investigated its effect on atopic dermatitis (AD). Following characterization, cytotoxicity, pro-inflammatory response and oxidative stress associated with boehmite were assessed, using TNF-α-induced keratinocytes and mast cells. In addition, therapeutic effects of boehmite, topically administered to Balb/c mice induced by 2,4-dinitrochlorobenzene (DNCB), were evaluated. Expression of cytokines (TLSP, IL-25 and IL-33) and the generation of ROS from keratinocytes induced by TNF-α were significantly inhibited by boehmite without affecting cell viability. MAPKs (ERK, JNK and p38) required for cytokine expression were suppressed by boehmite treatment. Up-regulation of cytokines (TSLP, IL-4, IL-5, IL-13, RANTES) in human mast cells treated with phorbol 12-myristate 13-acetate and calcium ionophore was also suppressed by boehmite. Boehmite improved the AD severity score, epidermal hyperplasia and transepidermal water loss in DNCB-induced AD-like lesions. Moreover, Th2-mediated cytokine expression, mast cell hyperplasia and destruction of the skin barrier were improved by boehmite treatment. Overall, we demonstrated that boehmite may potentially protect against AD.

Adjuvants in allergen-specific immunotherapy: modulating and enhancing the immune response

Allergen-specific immunotherapy (AIT) is the only treatment that can affect the natural course of allergic diseases such as allergic asthma, allergic rhinitis, and IgE-mediated food allergy. Adjuvants are used to induce a quicker, more potent, and longer-lasting immune response. Only 4 compounds are used as adjuvants in currently marketed AIT products: aluminum hydroxide, calcium phosphate, microcrystalline tyrosine (MCT), and monophosphoryl lipid A (MPL). The first 3 adjuvants are delivery systems with a depot effect, although they may also have immunomodulatory properties. These first-generation adjuvants are still widely used, especially aluminum hydroxide. However, aluminum is subject to limitations. MCT is the depot formulation of L-tyrosine; it enhances IgG production without inducing a significant increase in IgE, is biodegradable, and has good local and systemic tolerability. In turn, MPL is an immunostimulatory agent that is the only second-generation adjuvant currently used for AIT. In addition, multiple adjuvants are currently being studied, including immunostimulatory sequences (ISSs), nanoparticles (liposomes, virus-like particles, and biodegradable polymers), and phosphatidylserine derivatives. In a murine model of allergic bronchial inflammation by sensitization to olive pollen, the specific IgE level was significantly higher in sensitized mice treated with olive pollen and aluminum hydroxide. However, specific IgE levels were significantly reduced and bronchial hyperreactivity significantly improved in sensitized mice treated with olive pollen and bacterial derivatives (MPL or ISSs)

La inmunoterapia específica con alérgenos (ITE) es el único tratamiento con potencial para modificar la evolución natural de enfermedades alérgicas como el asma alérgica, la rinitis alérgica y la alergia a alimentos mediada por IgE. Los adyuvantes se usan para provocar una respuesta inmune más rápida, más potente y de mayor duración. Hasta ahora, solo cuatro compuestos se usan como adyuvantes en los productos de ITE comercializados actualmente: hidróxido de aluminio, fosfato cálcico, tirosina microcristalina (MCT) y monofosforil lípido A (MPL). Los tres primeros son sistemas de liberación retardada (efecto depot), aunque también podrían tener propiedades inmunomoduladoras. Estos adyuvantes de primera generación todavía se usan ampliamente, sobre todo el hidróxido de aluminio. Sin embargo, el aluminio tiene algunas limitaciones. MCT es la formulación de liberación retardada de la L-tirosina; aumenta la producción de IgG sin provocar un incremento significativo de IgE, es biodegradable y tiene una buena tolerabilidad local y sistémica. A su vez, MPL es un inmunoestimulador y es el único adyuvante de segunda generación usado actualmente en ITE. Además, hay múltiples adyuvantes en investigación, como las secuencias inmunoestimuladoras (SIE), nanopartículas (liposomas, partículas similares a virus y polímeros biodegradables) y derivados de la fosfatidilserina.En un modelo múrido de inflamación bronquial alérgica por sensibilización al polen de olivo, el nivel de IgE específica fue significativamente mayor en los animales sensibilizados tratados con polen de olivo e hidróxido de aluminio. Sin embargo, en los animales sensibilizados tratados con polen de olivo y derivados bacterianos (MPL o SIE) se observó una disminución significativa del nivel de IgE específica y una mejoría significativa de la hiperreactividad bronquial

Comparative study of adjuvants for allergen-specific immunotherapy in a murine model.

AIM: To compare the immunological and clinical changes induced by allergen-specific immunotherapy (AIT) using different adjuvants. MATERIALS & METHODS: Olea europaea pollen-sensitized mice were treated with olea plus aluminum hydroxide, calcium phosphate, monophosphoryl lipid A (MPL) or immunostimulatory sequences (ISS). RESULTS: Aluminum hydroxide seems to drive initially to a Th2-type response. Bacteria-derived adjuvants (MPL and ISS) skew the immune response toward Th1 and Treg pathways. Specific-IgE production was lower after AIT with MPL and ISS. Moreover, IgG2a production significantly increased in ISS-treated mice. Bacteria-derived adjuvants also improved the Th1 cytokine response due to IFN-γ higher secretion. In addition, they improved bronchial hyper-reactivity and lung inflammation. CONCLUSION: Bacteria-derived adjuvants may enhance the efficacy of AIT.

Electroacupuncture plus standard of care for managing refractory functional dyspepsia: protocol of a pragmatic trial with economic evaluation.

INTRODUCTION: This trial proposes to compare the effectiveness and cost-effectiveness of electroacupuncture (EA) plus on-demand gastrocaine with waiting list for EA plus on-demand gastrocaine in providing symptom relief and quality-of-life improvement among patients with functional dyspepsia (FD). METHODS AND ANALYSIS: This is a single-centre, pragmatic, randomised parallel-group, superiority trial comparing the outcomes of (1) EA plus on-demand gastrocaine group and (2) waiting list to EA plus on-demand gastrocaine group. 132 (66/arm) endoscopically confirmed, Helicobacter pylori-negative patients with FD will be recruited. Enrolled patients will respectively be receiving (1) 20 sessions of EA over 10 weeks plus on-demand gastrocaine; or (2) on-demand gastrocaine and being nominated on to a waiting list for EA, which entitles them 20 sessions of EA over 10 weeks after 12 weeks of waiting. The primary outcome will be the between-group difference in proportion of patients achieving adequate relief of symptoms over 12 weeks. The secondary outcomes will include patient-reported change in global symptoms and individual symptoms, Nepean Dyspepsia Index, Nutrient Drink Test, 9-item Patient Health Questionnaire (PHQ9), and 7-item Generalised Anxiety Disorder Scale (GAD7). Adverse events will be assessed formally. Results on direct medical costs and on the EuroQol (EQ-5D) questionnaire will also be used to assess cost-effectiveness. Analysis will follow the intention-to-treat principle using appropriate univariate and multivariate methods. A mixed model analysis taking into account missing data of these outcomes will be performed. Cost-effectiveness analysis will be performed using established approach. ETHICS AND DISSEMINATION: The study is supported by the Health and Medical Research Fund, Government of the Hong Kong Special Administrative Region of China. It has been approved by the Joint Chinese University of Hong Kong - New Territories East Cluster Clinical Research Ethics Committee. Results will be published in peer-reviewed journals and be disseminated in international conference. TRIAL REGISTRATION NUMBER: ChiCTR-IPC-15007109; Pre-result.

Effect of alginate in patients with GERD hiatal hernia matters.

Alginate-based formulations are frequently used as add-on proton pump inhibitor (PPI) therapy to help control of heartburn and regurgitation. There are limited data regarding the mechanisms and effects of alginate-based formulations. We aimed to evaluate the effects of the sodium alginate intake and its likely temporal relations on intraesophageal reflux events by MII-pH in patients with and without hiatal hernia (HH). Fifty GERD patients (18 with HH, 32 without HH) with heartburn or regurgitation once a week or more common were included. After combined multichannel intraluminal impedance and pH-metry (MII-pH) had been performed, all patients were asked to eat the same standard meal (double cheeseburger, 1 banana, 100 g regular yoghurt, and 200 mL water with total energy value of 744 kcal: 37.6% of carbohydrates, 21.2% of proteins, and 41.2% of lipids) during two consecutive days. On separate random two consecutive days, all patients took 10 mL of sodium alginate (GA; Gaviscon Advance; Reckitt Benckiser Healthcare, Hull, UK) or 10 mL of water, 30 minutes after the refluxogenic meal. After eating refluxogenic meal, patients were examined ½ hour for basal conditions, 1 hour in upright, and 1 hour in supine positions. Alginate significantly decreased acid reflux after intake at the first hour in comparison to water in patients with HH (6.1 vs. 13.7, P = 0.004) and without HH (3.5 vs. 5.5, P = 0.001). Weakly acid reflux were increased at the first hour in patients with HH (3.4 vs. 1.3, P = 0.019) and without HH (1.7 vs. 5, P = 0.02) compared to water. There was no distinctive effect of alginate on the height of proximal migration of reflux events in patients with HH and without HH. Alginate decreases acid reflux events within a limited time period, especially at the first hour both in patients with and without HH. Alginate has no effect on the height of reflux events along the esophagus both in patients with and without HH.

Cómo estimar la eficacia de un captor del fósforo / How to assess the efficacy of phosphate binders

Antecedentes y objetivos: Es difícil estimar clínicamente la eficacia de los captores de fósforo (CP). Este estudio analiza los cambios que se producen en la fosfatemia y excreción urinaria de fósforo tras la administración de CP a pacientes con enfermedad renal crónica, y la utilidad de la relación entre la excreción urinaria de fósforo y la tasa de catabolismo proteico (Po/TCP) en la estimación de la eficacia de estos fármacos. Métodos: Estudio retrospectivo de observación en una cohorte de pacientes adultos con enfermedad renal crónica en estadios 4-5. Se compararon parámetros bioquímicos basales y 45-60 días después de un tratamiento con dieta baja en fósforo más CP (subgrupo «captor»=260 pacientes) o solo con los consejos dietéticos (subgrupo «control»=79 pacientes). Resultados: La carga de fósforo (excreción urinaria total) por unidad de función renal (Po/GFR) fue el parámetro mejor relacionado con la fosfatemia (R2=0,61). La cifra media de Po/TCP fue de 8,2±2,3mg de fósforo por gramo de proteína. Tras la administración de CP, la fosfatemia descendió un 11%, la fosfaturia un 22%, la tasa de catabolismo proteico un 7% y la Po/TCP un 15%. En el subgrupo control la Po/TCP se incrementó un 20%. La excreción urinaria de fósforo y de nitrógeno ureico se correlacionaron fuertemente de forma lineal antes y después del tratamiento con CP o tras los consejos dietéticos en el subgrupo control. Conclusiones: La Po/TCP es un parámetro que podría reflejar la absorción intestinal de fósforo y, por tanto, sus variaciones tras la administración de CP podrían servir para estimar la eficacia de estos fármacos (AU)

Background and aims: The efficacy of phosphate binders is difficult to be estimated clinically. This study analyzes the changes in serum phosphate and urinary phosphate excretion after the prescription of phosphate binders (PB) in patients with chronic kidney disease stage 4-5 pre-dialysis, and the usefulness of the ratio between total urinary phosphate and protein catabolic rate (Pu/PCR) for estimating the efficacy of PB. Methods: This retrospective observational cohort study included adult chronic kidney disease patients. Biochemical parameters were determined baseline and after 45-60 days on a low phosphate diet plus PB (‘binder’ subgroup=260 patients) or only with dietary advice (‘control’ subgroup=79 patients). Results: Phosphate load (total urinary excretion) per unit of renal function (Pu/GFR) was the best parameter correlated with serum phosphate levels (R2=0.61). Mean±SD level of Pu/PCR was 8.2±2.3mg of urinary phosphate per each g of estimated protein intake. After treatment with PB, serum phosphate levels decreased by 11%, urinary phosphate 22%, protein catabolic rate 7%, and Pu/PCR 15%. In the control subgroup, Pu/PCR increased by 20%. Urinary phosphate and urea nitrogen excretion correlated strongly, both baseline and after PB or dietary advice. Conclusions: The proposed parameter Pu/PCR may reflect the rate of intestinal phosphate absorption, and therefore, its variations after PB prescription may be a useful tool for estimating the pharmacological efficacy of these drugs (AU)

Interventions for Treating Heartburn in Pregnancy.

Editor's note: This is a summary of a nursing care-related systematic review from the Cochrane Library.

Novel and Effective Almagate Enema for Hemorrhagic Chronic Radiation Proctitis and Risk Factors for Fistula Development.

Radiation proctitis is a common complication after radiotherapy for pelvic malignant tumors. This study was conducted to assess the efficacy of novel almagate enemas in hemorrhagic chronic radiation proctitis (CRP) and evaluate risk factors related to rectal deep ulcer or fistula secondary to CRP. All patients underwent a colonoscopy to confirm the diagnosis of CRP and symptoms were graded. Typical endoscopic and pathological images, risk factors, and quality of life were also recorded. A total of 59 patients were enrolled. Gynecological cancers composed 93.1% of the primary malignancies. Complete or obvious reduction of bleeding was observed in 90% (53/59) patients after almagate enema. The mean score of bleeding improved from 2.17 to 0.83 (P<0.001) after the enemas. The mean response time was 12 days. No adverse effects were found. Moreover, long-term successful rate in controlling bleeding was 69% and the quality of life was dramatically improved (P=0.001). The efficacy was equivalent to rectal sucralfate, but the almagate with its antacid properties acted more rapidly than sucralfate. Furthermore, we firstly found that moderate to severe anemia was the risk factor of CRP patients who developed rectal deep ulcer or fistulas (P= 0.015). We also found abnormal hyaline-like thick wall vessels, which revealed endarteritis obliterans and the fibrosis underlying this disease. These findings indicate that almagate enema is a novel effective, rapid and well-tolerated method for hemorrhagic CRP. Moderate to severe anemia is a risk factor for deep ulceration or fistula.